PURPOSE: Four years ago, I proposed a new model of the immune system (the Danger model) based on the assumption that the immune system?s function is to discriminate between dangerous and harmless things rather than self and non-self. Because this model has tremendous implications for such subjects as cancer, transplantation, neonatal vacccines, parasitology, and autoimmunity, we have begun to test its basic premises and its applicability in several areas. RESULTS FROM THE PAST YEAR: 1) TESTING THE BASIC PREMISES: A) Danger signals from injured tissues initiate immune responses. We found that 1) Injured tissues (but not healthy or apoptotic tissues) release both pre-packaged and newly synthesized Danger signals that can activate resting dendritic cells. 2) The range of function of activated dendritic cells can be further modified by interactions with T helper cells or virus. B) Tissue signals also influence the effector class of an immune response: 1) The immune response to antigens given orally is shifted to a TH2 class. This shift does not require the presence of B cells or M cells. Cells from a shifted animal can impose the shift on naive recipients and on cells responding to other antigens given simultaneously. 2) The class of immune response to Leishmania Major, which differs in different mouse strains, correlates with the organs to which the parasite disseminates. This difference in dissemination is independent of T cells or B cells and appears to be an intrinsic difference in the way the parasite infects the different mice. Thus the differences in immune effector class may occur because of the location in which the response is initiated. 2) TRANSPLANTATION: A) Orthotopic liver transplants: 1) Livers transplanted across major histocompatibility barriers are accepted. With time, some of the recipients become tolerant of donor MHC class I molecules, as assayed by CTL activity, but not of donor MHC class II, measured in a proliferation assay. B) Skin grafts to immuno-incompetent mice. 1) Donor dendritic cells from a transplanted skin can remain viable and active for months after the transplant. If the graft is removed, the dendritic cells nevertheless remain in the draining nodes for weeks. 2) T cells maturing in an animal carrying a long-healed skin graft nevertheless reject that graft, showing that the T cells do not exit the thymus in a tolerizable only state. 3) MATERNAL/FETAL INTERACTIONS. The Danger model suggests that mothers do not reject their fetuses simply because the fetuses do not look dangerous. However, microvascular accidents occuring in the placenta can sometimes send damaged and healthy fetal cells into the circulation of the mother. Using quantitative PCR for the Y chromosome we followed the traffic of male cells in the organs of pregnant mice. This traffic was very sporadic and the cells were rejected by the maternal immune system while the fetus itself was not.